Controlling Gene Expression with Synthetic Cell-Penetrating Transcription Factors

Project Information

SynTra

Grant agreement ID: 101039354

DOI

10.3030/101039354

EC signature date 28 April 2022

Start date 1 June 2022

End date 31 May 2027

Funded under

• European Research Council (ERC)

Total cost

€ 1 851 328,00

EU contribution

€ 1 851 328,00

Coordinated by

UNIVERSITEIT LEIDEN
Netherlands

Periodic Reporting for period 1 - SynTra (Controlling Gene Expression with Synthetic Cell-Penetrating Transcription Factors)

Reporting period: 2022-06-01 to 2024-11-30

Summary of the context and overall objectives of the project

The ERC StG project SynTra aims to develop synthetic miniproteins able to enter cells, bind to specific DNA sequences and modulate disease related gene transcription. The Pomplun Lab proposes to utilize a combination of rational design, combinatorial chemistry and synthetic protein modification technology to achieve this goal.
Targeting specific DNA sequences is challenging when utilizing small molecules. On the other hand, macromolecules (or macromolecular complexes), such as transcription factor proteins that are able to recognizes specific DNA sequences, are not able to enter cells. We propose the development of chemically engineered transcription factor analogs able to enter cells and the cell nucleus and bind to DNA. By targeting specific disease related sequences, such as the enhance box of the oncogenic transcription factor MYC, we aim to tackle gene related disease development.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

To date we tested the suitability of different natural transcription factor scaffolds for function retaining chemical modifications. We identified basic helix loop helix transcription factors as suitable structures, and identified a number of chemical modifications that a) maintain the proteins DNA binding activity and b) enable these synthetic proteins to enter cells. In a number of functional in vitro and in cell assays we show how our miniproteins can modulate disease related gene transcription. In particular, we identified variants that can inhibit the oncogenic transcription factor MYC with a high potency.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The lead compound developed within this ERC StG project is a highly promising candidate for the development of advanced therapeutics to treat MYC driven cancers. We plan to proceed to test this compound in more advanced systems such as MYC dependet tumor organoids and mouse models, in the near future.